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Genetic variation and its role in health and pharmacology

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Genetic variation and its role in health and pharmacology

  1. 1. GENETIC VARIATION AND ITS ROLE IN HEALTH AND PHARMACOLOGY PRESENTED BY:-GAGANDEEP JAISWAL (M. PHARM. PHARMACOLOGY) 1 Department of Pharmaceutical Sciences And Technology,MRSPTU
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  3. 3. Key Terms:- • Genetic variation:- In a very simple language, genetic variation is a measure of the variation that exists in the genetic makeup of individuals within population. variation in alleles of genes that occurs both within and among populations • Genetic Diversity: the level of biodiversity, refers to the total number of genetic characteristics in the genetic makeup of a species • Crossing Over: the exchange of genetic material between homologous chromosomes that results in recombinant chromosomes • Phenotypic Variation: variation (due to underlying heritable genetic variation); a fundamental prerequisite for evolution by natural selection • Genetic Variation: variation in alleles of genes that occurs both within and among populations • Alleles:-each of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome. • Natural Selection:- the process whereby organisms better adapted to their environment tend to survive and produce more offspring. The theory of its action was first fully expounded by Charles Darwin, and it is now regarded as be the main process that brings about evolution. 3
  4. 4. WHAT IS GENETIC VARIATION?  Genetic variation generally refers to the differences in genes between individual members of a population, or the frequency in which the various gene types are expressed. Genetic variation is incredibly important for the survival and adaptation of a species, as it helps in terms of natural selection and evolution.  Individuals of a species have similar characteristics but they are rarely identical, the difference between them is called variation.  In genetic variation, the genes of organisms within a population change. Gene alleles determine distinct traits that can be passed on from parents to offspring. Gene variation is important to the process of natural selection. The genetic variations that arise in a population happen by chance, but the process of natural selection does not. 4
  5. 5. GENE ALLELES DETERMINES THE DISTINCT TRAITS OF AN INDIVIDIUAL 5
  6. 6. Sources of Genetic Variation • Gene duplication, mutation, or other processes can produce new genes and alleles and increase genetic variation. New genetic variation can be created within generations in a population, so a population with rapid reproduction rates will probably have high genetic variation. However, existing genes can be arranged in new ways from chromosomal crossing over and recombination in sexual reproduction. Overall, the main sources of genetic variation are the formation of new alleles, the altering of gene number or position, rapid reproduction, and sexual reproduction. 6
  7. 7. Causes of Genetic Variation • Genetic variation occurs mainly through DNA mutation, gene flow , crossing over and sexual reproduction. Due to the fact that environments are unstable, populations that are genetically variable will be able to adapt to changing situations better than those that do not contain genetic variation. Gene flow and sexual reproduction reshuffle alleles within a population, giving offspring combinations which differ from their parents and from others. Nonrandom Mating and Environmental Variance are some other factors which leads to the genetic variation. 7
  8. 8. Causes In Detail A. DNA Mutation:-Mutations are changes to an organism’s DNA and are an important driver of diversity in populations. Species evolve because of the accumulation of mutations that occur over time. The appearance of new mutations is the most common way to introduce novel genotypic and phenotypic variance. Some mutations are unfavorable or harmful and are quickly eliminated from the population by natural selection. Others are beneficial and will spread through the population. Whether or not a mutation is beneficial or harmful is determined by whether it helps an organism survive to sexual maturity and reproduce. Some mutations have no effect on an organism and can linger, unaffected by natural selection, in the genome while others can have a dramatic effect on a gene and the resulting phenotype. 8
  9. 9. Mutation in a garden rose: A mutation has caused this garden moss rose to produce flowers of different colors. This mutation has introduce a new allele into the population that increases genetic variation and may be passed on the next generation.9
  10. 10. B. Gene Flow:-An important evolutionary force is gene flow: the flow of alleles in and out of a population due to the migration of individuals or gametes. While some populations are fairly stable, others experience more movement and fluctuation.  Many plants, for example, send their pollen by wind, insects, or birds to pollinate other populations of the same species some distance away. Even a population that may initially appear to be stable, such as a pride of lions, can receive new genetic variation as developing males leave their mothers to form new prides with genetically-unrelated females.  This variable flow of individuals in and out of the group not only changes the gene structure of the population, but can also introduce new genetic variation to populations in different geological locations and habitats.  Maintained gene flow between two populations can also lead to a combination of the two gene pools, reducing the genetic variation between the two groups. Gene flow strongly acts against speciation, by recombining the gene pools of the groups, and thus, repairing the developing differences in genetic variation that would have led to full speciation and creation of daughter species.  For example, if a species of grass grows on both sides of a highway, pollen is likely to be transported from one side to the other and vice versa. If this pollen is able to fertilize the plant where it ends up and produce viable offspring, then the alleles in the pollen have effectively linked the population on one side of the highway with the other. 10
  11. 11. Gene flow: Gene flow can occur when an individual travels from one geographic location to another. 11
  12. 12. C. Crossing over and sexual reproduction:- Chromosomal crossover (or crossing over) is the exchange of genetic material between 2 homologous chromosomes non-sister chromatids that results in recombinant chromosomes during sexual reproduction. Crossing over accounts for genetic variation, because due to the swapping of genetic material during crossing over, the chromatids held together by the centromere are no longer identical. Sexual reproduction promotes genetic variation by producing different gene combinations. Meiosis is the process by which sex cells or gametes are created. Genetic variation occurs as alleles in gametes are separated and randomly united upon fertilization. 12
  13. 13. Crossing over and recombination during meiosis 13
  14. 14. Nonrandom Mating and Environmental Variance  Population structure can be altered by nonrandom mating (the preference of certain individuals for mates) as well as the environment.  Nonrandom mating can occur when individuals prefer mates with particular superior physical characteristics or by the preference of individuals to mate with individuals similar to themselves. 14 Assortative mating in the American Robin: The American Robin may practice assortative mating on plumage color, a melanin based trait, and mate with other robins who have the most similar shade of color. However, there may also be some sexual selection for more vibrant plumage which indicates health and reproductive performance.
  15. 15. Environmental Variance • Genes are not the only players involved in determining population variation. Phenotypes are also influenced by other factors, such as the environment. 15 Temperature-dependent sex determination: The sex of the American alligator (Alligator mississippiensis) is determined by the temperature at which the eggs are incubated. Eggs incubated at 30 degrees C produce females, and eggs incubated at 33 degrees C produce males.
  16. 16. Genetic variation in the shells of Donax variabilis: An enormous amount of phenotypic variation exists in the shells of Donax varabilis16
  17. 17. Human genetic variation • Human genetic variation is the genetic differences in and among populations. • There may be multiple variants of any given gene in the human population (alleles), a situation called polymorphism. • No two humans are genetically identical. Even monozygotic twins (who develop from one zygote) have infrequent genetic differences due to mutations occurring during development. • The study of human genetic variation has evolutionary significance and medical applications. It can help scientists understand ancient human population migrations as well as how human groups are biologically related to one another. • For medicine, study of human genetic variation may be important because some disease-causing alleles occur more often in people from specific geographic regions. New findings show that each human has on average 60 new mutations compared to their parents. 17
  18. 18. Role of genetic variation in health and pharmacology • Differences in allele frequencies contribute to group differences in the incidence of some monogenic diseases, and they may contribute to differences in the incidence of some common diseases. For the monogenic diseases, the frequency of causative alleles usually correlates best with ancestry, whether familial (for example, Ellis-van Creveld syndromeamong the Pennsylvania Amish), ethnic (Tay- Sachs disease among Ashkenazi Jewish populations), or geographical (hemoglobinopathies among people with ancestors who lived in malarial regions). To the extent that ancestry corresponds with racial or ethnic groups or subgroups, the incidence of monogenic diseases can differ between groups categorized by race or ethnicity, and health-care professionals typically take these patterns into account in making diagnoses. • Some other variations on the other hand are beneficial to human, as they prevent certain diseases and increase the chance to adapt to the environment. For example, mutation in CCR5 gene that protects against AIDS. CCR5 gene is absent on the surface of cell due to mutation. Without CCR5 gene on the surface, there is nothing for HIV viruses to grab on and bind into. Therefore the mutation on CCR5 gene decreases the chance of an individual’s risk with AIDS. The mutation in CCR5 is also quite popular in certain areas, with more than 14% of the population carry the mutation in Europe and about 6-10% in Asia and North Afriac. 18
  19. 19. HIV Attachment 19
  20. 20. • Apart from mutations, many genes that may have aided humans in ancient times plague humans today. For example, it is suspected that genes that allow humans to more efficiently process food are those that make people susceptible to obesity and diabetes today. • As far as pharmacological role of genetic variation is concerned, Variability in drug efficacy and adverse effects are observed in clinical practice • Drug-related genes show high extent of genetic variability across millions of individuals • Cancer drug target genes have many germ line functional-variants:- Especially in cancer therapy, genetic variation in drug targets has been recognized to play a crucial role for treatment success. While some cancer drugs do not act in the tumor tissue, the cancer drug’s primary site of action usually is in the tumor, whose genome contains tumor specific somatic variants as well as a subset of patient-specific germ line variants30. Information on somatic variants from tumor samples is thus increasingly used to enable research on drug design and to implement stratified or personalized cancer therapy. • For instance, the DRPs of taxanes (docetaxel, paclitaxel, and cabazitaxel) are 30 percentage points higher in the cohorts of South Asian and European ancestry compared to the cohort of African ancestry (DRPSAS/NFE = 85% vs DRPAFR = 45%) due to functional variants in the four taxane targets, TUBB1, MAP2, MAP4, and MAPT. 20
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  22. 22. • Dopamine D2 (encoded by the DRD2 gene) receptors are primarily expressed in the terminal regions of dopaminergic neurons. Studies in DRD2-null mice suggest that the D2 receptor functions as an auto receptor on dopamine neurons. The most well-established polymorphism in the DRD2 gene is Taq1A, a C>T substitution located 10kb (kilobases)3’ of the DRD2 gene. This Taq1A polymorphism is associated with an increased risk for multiple types of substance abuse , including heroin use , cocaine dependency , psychostimulant polysubstance abuse , and smoking. • In addition to the dopaminergic system, nicotinic acetylcholine receptors have been implicated in nicotine reward and dependency. Two non synonymous SNPs on exon5 (rs1044396/1629G>T andrs1044397/1659G>A)of the gene encoding for the α4 subunit of the nicotinic acetylcholine receptor (CHRNA4) were associated with a lower risk of nicotine dependency in Chinese men (96), which was recently replicated in a European population. A G>A variant, rs2236196, in the 3 untranslated region of CHRNA4, was associated with greater subjective effects of nicotine and higher risk of nicotine dependency. 22
  23. 23. IS GENETIC DIVERSITY GOOD OR BAD?  Genetic diversity is, in general, a good thing for a population, for a simple reason: adaptation via natural selection depends on the existence of variation (there cannot be selection in the absence of alternatives). Other things being equal, a population possessing a greater amount of genetic diversity has a greater probability of already possessing adaptive alleles that might be necessary to meet new environmental challenges (e.g., pathogens).  Even the boundaries between the useful/neutral/deleterious categories are blurred. Deleterious anaemia-causing mutations are known to have benefits of malaria- resistance.  Neutral variants may be “useful” ones in waiting: for example, lactase persistent mutants may have existed in the human species for hundreds of thousands of years, appearing and re-appearing by mutation, but it is when they encountered cow’s milk and the need to drink it that they shifted from “neutral” to “useful”.  And, even useful alleles can cease to be so, e.g., the eradication of swamps and malaria in Greece has removed the benefit of malaria-resistence, and left only the harm of anaemia. 23
  24. 24. References o https://courses.lumenlearning.com/boundless- biology/chapter/population-genetics o https://www.thoughtco.com/genetic-variation-373457 o https://www.genome.gov/27570931/april-06-human- genomic-variation o https://en.wikipedia.org/wiki/Human_genetic_variation# Health o https://www.annualreviews.org/doi/10.1146/annurev.ph armtox.010909.105826 o https://genomemedicine.biomedcentral.com/articles/10. 1186/s13073-017-0502-5 24
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Notas del editor

  •  a Availability of documented pharmacogenetic associations for 1236 FDA-approved drugs in public repositories such as the PharmGKB database [22] (left) is less abundant than functional variants observed in the population for the drug target genes (right). b, c Examples of known and novel genetic variants (green) in the target genes of warfarin and taxanes that could affect drug efficacy due to effects on the binding site (ligand highlighted in orange)
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